1. Field of the Invention
This invention generally relates to a class of chemicals that specifically activate the cold receptors and therapeutic use of these chemicals. This invention more particularly relates to therapeutic compositions eliciting long-lasting cooling or soothing properties, particularly when formulated for delivery to suppress the sensations of itch and pain, such as for delivery to inflamed skin, to the mucous membranes of the anogenital areas, and to the enteric mucosa. The particularly preferred embodiment compositions comprise “icilin”, a 1,2,3,6-tetrahydropyrimidine-2-one compound.
2. Description of Related Art
Human awareness of the external environment is conveyed by specialized organs for sight, smell, sound, taste, touch and pressure. In addition to these sensory modalities, there are present in the skin, mucous membranes, and gut, specialized nerve endings for detecting heat, cold, pain and itch.
Sensory mechanisms and inflammation. Small-diameter nerve fibers, mostly unmyelinated, carry the afferent nerve signals that are decoded in the brain as sensations of heat, cold, pain and itch. On the nerve fibers are specialized receptors that respond to temperature changes and to chemicals that produce sensations of heat and cold, such as capsaicin the active ingredient of chili peppers and menthol the active ingredient of mentha leaves. The intense stimulation of heat and pain fibers can cause the concurrent release of neuroactive peptides such as substance P from the sensory nerves and this release exacerbates tissue injury, a phenomenon known as “neurogenic inflammation.”
Anti-inflammatory effects of cold-receptor activation. The ability of ice applied to the skin or to the orbit to suppress the pain of burns or other forms of traumatic injury is well known. An ice cube in the mouth will also suppress a toothache. The precise mechanisms of pain relief by cold are not clear but it has been shown in animal experiments that the discharge of pain fiber afferents are decreased by contact with surfaces of solids with a low temperature such as ice. Menthol, a chemical that activates the cold receptor, does not suppress severe pain, but the cooling sensations that it evokes on the skin and mucous membranes are refreshing and counteracts heat and irritation. Thus, menthol is used as a component in a wide range of toiletries, liniments and lotions for topical application on the skin, and as a flavoring and refreshing agent in foodstuffs, beverages, toothpastes, skin rubs, and mouthwashes. Menthol is also used as a tobacco additive for producing a cool sensation in the mouth and upper respiratory tract when smoking.
Background on icilin. 1,2,3,6-Tetrahydropyrimidine-2-one compounds were described in U.S. Pat. No. 3,821,221(inventors C. Podesva and J. M. Do Nascimento., Jun. 28, 1974). These compounds were thought to have depressant and/or stimulant effects on the central nervous system. In 1972, an abstract described a compound in this series called AG-3-5 (1[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one). This prototype elicited a syndrome of “wet dog shake behavior” in rats and monkeys accompanied by hyperthermia, hyperactivity and ptosis. Wei (Chemical stimulants of shaking behavior. Journal of Pharmacy and Pharmacology 28: 722-724, 1976) provided the first detailed report of the actions of AG-3-5 in animals and noted that shaking behavior similar to those of a dog when wet could be evoked in various laboratory animals such as the rat, mouse, cat, dog, gerbils, guinea pigs and hamsters. Subsequently, Wei (Pharmacological aspects of shaking behavior produced by AG-3-5, TRH, and morphine withdrawal. Federation Proceedings 40: 1491-1496, 1981) reported that 0.1 mg of AG-3-5 applied to the dorsum of the tongue elicited prickling sensations of cold and ingestion of 6 mg, on one occasion out of three, produced sensations of coolness on the cheeks and on the inner surfaces of the arms and legs. It was hypothesized that AG-3-5 may produce specific activation of receptors for cold, and that stimulation of these receptors accounted for the shaking seen in laboratory animals. In a subsequent publication E. T. Wei and D. A. Seid. AG-3-5: A chemical producing sensations of cold Journal of Pharmacy and Pharmacology 35: 110-112, 1983) the effects of AG-3-5 on shaking behavior in the rat were compared to those of menthol and AG-3-5 was shown to be 400 times more potent than menthol on a molar basis on this behavioral endpoint. AG-3-5 was less toxic than menthol, as measured by the oral median lethal dose in rats. AG-3-5 was named icilin because of its cold-producing properties.
Recently, two independent groups simultaneously cloned a biological macromolecule (called receptor) from trigeminal sensory neurons of the rat. These receptors belong to the transient receptor potential (TRP) family of ion channels and responded to cold temperature and to menthol. Using a sample provided by Wei, McKemy et al. (Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52-58, 2002) showed that icilin was about 200 times more potent than menthol in eliciting ion channel current changes in the cloned and transfected TRP(M8) receptor. The ion permeability changes elicited in transfected cells were more robust with icilin than those elicited by menthol, and the presence of extracellular calcium was required for activity. Menthol currents did not require extracellular calcium.
The chemical structure of icilin bears little similarity to that of menthol; the former one being a pyrmidine-2-one attached to two phenyl rings, and the latter a cyclohexanol derivative. Activation of the TRP(M8) receptor on the neuronal membrane may lead to depolarization of the sensory nerve ending and send action potentials towards the spinal cord and brain that are eventually recognized as psychic signals of cold.
Most of the known cooling agents used in commerce as consumer products to reduce irritation in the skin and mucous membranes have chemical structures similar to menthol and are based on a cyclohexanol template. For example, Vicks Corporation, a division of Proctor and Gamble, sells a variety of products for upper respiratory ailments, including the common cold, cough and bronchitis. The active ingredient(s) in VapoSteam® is camphor (a cough suppressant with chemical structure similar to menthol) and in VapoRub® menthol and camphor. Other ingredients used are: Vapor Inhaler® (levamphetamine, as a nasal decongestant), NyQuill Cough® (dextromethorphan, an antitussive and an antihistamine). Vicks 44® anticough syrup also contains dextromethorphan as the primary antitussive.
Although drugs such as camphor, menthol, phenol, salicylic acid, tar, capsaicin, and petrolatum are part of dermatological preparations to reduce skin irritation, they have limited anti-pruritic effect and are often of short duration. Devices to physically lower tissue temperature with ice probes have also been used for anorectal discomfort (U.S. Pat. No. 5,800,485).
A need exists for therapeutic compositions useful on inflamed skin and the mucous membranes of the anogenital areas for itching and for the discomforts of hemorrhoids.